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Bending the Curve Trial by Trial
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Anus (digestive system)

Anal cancer

A rare HPV-linked cancer: chemoradiation replaced surgery as primary treatment; PD-1 therapy now has a first-line role in advanced disease.

5-year relative survival · United States, SEER 8 registries

63.28%→71.27%

1975 (observed value) to 2018 (observed value; last observed year in the table). Read these with the caveats under “Then and now”.Source

25 milestones, by decade

  • A 2026 historical review states that in the United States abdominoperineal resection was the standard primary treatment before the mid-1980s. In a 1984 evaluation Nigro reported that his group began preoperative radiation and chemotherapy in 1972 and that by 1975 radical operation was no longer done routinely. Two randomised trials then tested adding fluorouracil and mitomycin to radiotherapy. In the original ACT I report (585 randomised; median follow-up 42 months) local failure, the main endpoint, occurred in 59% of those analysed with radiotherapy alone and 36% with chemoradiation (relative risk 0.54; 95% CI 0.42 to 0.69); in EORTC 22861 (110 randomised) complete remission was 54% and 80%. At a median follow-up of 13.1 years ACT I found no statistically significant overall survival difference (hazard ratio 0.86; 95% CI 0.70 to 1.04), and EORTC 22861 reported similar survival in the two arms.
  • ANCHOR randomised people living with HIV who were aged 35 or older and had biopsy-proven high-grade anal precancer (HSIL) to have the lesions treated or to be monitored without treatment. Of 4,446 analysed, anal cancer was diagnosed in 9 people in the treatment group (173 per 100,000 person-years; 95% CI 90 to 332) and 21 in the monitoring group (402 per 100,000 person-years; 95% CI 262 to 616); the rate was 57% lower with treatment (95% CI 6 to 80; P = 0.03). Median follow-up was 25.8 months. The trial tested treating a precancer that had already been found, not screening itself, and enrolled only people living with HIV.
  • POD1UM-303 randomised 308 adults with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal who had not had systemic chemotherapy to carboplatin-paclitaxel with retifanlimab or with placebo. Median progression-free survival was 9.3 against 7.4 months (hazard ratio 0.63; 95% CI 0.47 to 0.84). On 15 May 2025 the FDA approved retifanlimab with carboplatin and paclitaxel as first-line treatment of this population (the same letter also approved single-agent use after platinum-based chemotherapy, for which the label reports a separate single-arm study, POD1UM-202). In the final overall survival analysis the medians were 32.8 and 22.2 months (hazard ratio 0.75; 95% CI 0.55 to 1.01); the FDA label of May 2026 states that the overall survival results were not statistically significant.

Evidence current to October 2026 · Checked against primary sources to the extent possible

A guided tour of 10 milestones. You can pause or step through it yourself.

Filter milestonesshowing all 25
Treatment type
Setting

The age of rays

  1. 1941 · Origin · UnderstandingSt Mark's analysis of 55 squamous carcinomas of anus and anal canalIn 1941 Gabriel analysed 55 squamous cell cancers of the anus and anal canal admitted to St Mark's Hospital between 1922 and 1940. He graded them as low, medium or high grade, described differences by sex and site, and advised biopsy and grading before choosing treatment.Gabriel (Proc R Soc Med 1941): 55 squamous-cell carcinomas of the anus and anal canal admitted to St Mark's Hospital 1922-1940, 3.35% of all rectal, anal canal and anal cancers admitted; 27 males, 28 females; mean age 61.7 years. Three grades; best results in early low-grade cases treated by interstitial radium needling; three five-year survivors in medium and high grades, all after excision of the rectum.

Chemotherapy

  1. 1974 · Treatment · RadiationNigro: combined chemotherapy and radiation for anal canal cancerIn 1974 Nigro and colleagues published a preliminary report of combined chemotherapy and radiation for cancer of the anal canal. In 1984 Nigro wrote that by 1975 radical surgery was no longer done routinely, and that radiation and chemotherapy alone appeared at least as effective as radical surgery in most people. A 2026 review calls the 1974 study a landmark.Nigro et al, Dis Colon Rectum 1974 (preliminary report; no abstract). Later series: 19 patients treated with chemotherapy and radiation then appropriate surgery (1981); 104 patients, 44 treated by the author's group and the rest reported by questionnaire (1984), with radical operation not done routinely by 1975. A 2026 review describes the schedule as preoperative fluorouracil and mitomycin C with 30 Gy. Case series; no randomised comparison.
  2. 1975 · Understanding · UnderstandingAnal cancer staging: Paradis 1975 and AJCC 8th edition TNMIn 1975 a surgical series presented a staging system for anal cancer; a 2026 historical review describes no universally accepted system in that era. The AJCC 8th edition stages anal canal cancer by tumour size, nodes and distant spread. In a large chemoradiation trial, tumour-node category predicted survival, relapse and colostomy failure.Paradis (Surg Gynecol Obstet 1975) presented a staging system for anal carcinoma. AJCC 8th edition TNM as printed in NCI PDQ: T1 up to 2 cm, T2 over 2 to 5 cm, T3 over 5 cm, T4 invading adjacent organs; N1 inguinal, mesorectal or iliac nodes; stage 0 is HSIL (Tis). RTOG 98-11 (Gunderson 2013): 620 analysable; OS, DFS and LRF P<.0001 across TN categories; 3-year colostomy failure 11% for T2N0 and T2N+, 26% for T4N0.

Molecular origins

  1. 1987 · Understanding · Understanding⚑ needs reviewHPV 16 DNA in anal squamous cell carcinoma, 1987 to 1989A 1987 Lancet letter titled 'Human papillomavirus type 16 DNA in anal squamous cell carcinoma' has no abstract. A 1989 series found HPV 16 DNA in 23 of 41 such cancers and in no non-malignant anal tissue; another 1989 study described anal precancer (AIN) as a possible parallel to cervical precancer.Palmer (Lancet 1987 letter): HPV 16 DNA in anal squamous cell carcinoma (title only; no abstract). Palmer (Dis Colon Rectum 1989): 45 primary anal malignancies tested by Southern and dot blot; HPV 16 DNA in 23 of 41 squamous cell carcinomas (56%), HPV 18 in 2 of 41 (5%), HPV 6 or 11 in none. Scholefield (Lancet 1989): AIN in 23 of 82 patients with anal HPV infection; 17 of 28 homosexual vs 1 of 26 heterosexual men.
  2. 1987 · Understanding · UnderstandingCase-control studies link anal cancer to sexual history and HPVTwo case-control studies compared people with anal cancer with people without it. A 1987 study linked anal cancer to a history of receptive anal intercourse in men, to genital warts and to smoking. A 1997 study in Denmark and Sweden found high-risk HPV types, notably HPV 16, in most anal cancer specimens tested but in no rectal adenocarcinomas.Daling (NEJM 1987): 148 people with anal cancer vs 166 colon-cancer controls; relative risk 33.1 (95% CI 4.0 to 272.1) for receptive anal intercourse in men, 1.8 (0.7 to 4.2) for anal intercourse in women; current smoking 7.7 in women, 9.4 in men. Frisch (NEJM 1997, Denmark and Sweden): 324 women and 93 men, 534 rectal-adenocarcinoma and 554 population controls; high-risk HPV, notably HPV 16, in 84% of anal-cancer specimens tested.
  3. 1989 · Treatment · ChemotherapyPlatinum-fluoropyrimidine chemotherapy in metastatic anal cancerA 1989 case-report paper described cisplatin with a fluoropyrimidine for liver metastases from anal canal cancer, and a 1999 French series of 19 people treated between 1985 and 1996 reported tumour responses in about two of three evaluable patients. These small uncontrolled reports are early evidence for platinum-fluoropyrimidine chemotherapy in metastatic anal cancer.Series, not a trial. Faivre 1999 (Gustave-Roussy, English abstract): 19 patients with metastatic squamous-cell anal cancer treated 1985-1996 with cisplatin 100 mg/m2 on day 2 plus continuous-infusion fluorouracil every 4 weeks; 18 evaluable. Response rate 66% as printed (1 complete, 11 partial); median survival 34.5 months, actuarial survival 62.2% at 1 year and 32.2% at 5 years. Ajani 1989: case reports (title only).
  4. 1996 · Treatment · RadiationACT I and EORTC 22861: radiotherapy alone vs chemoradiationIn the 1990s two randomised trials compared radiotherapy alone with radiotherapy plus fluorouracil and mitomycin for anal cancer. In the larger UK trial, local failure occurred in 59 in 100 people given radiotherapy alone and 36 in 100 given chemoradiation. In the European trial, complete remission rose from 54 to 80 in 100. Neither trial reported an overall survival advantage.ACT I (N=585; 45 Gy with or without fluorouracil and mitomycin): local failure 59% vs 36% (relative risk 0.54, 95% CI 0.42-0.69; p<0.0001); death from anal cancer 0.71 (0.53-0.95); overall survival 0.86 (0.67-1.11; p=0.25). EORTC 22861 (N=110): complete remission 54% vs 80%; locoregional control p=.02; colostomy-free interval p=.002. ACT I at 13.1 years: locoregional relapse HR 0.46 (0.35-0.60); overall survival HR 0.86 (0.70-1.04).
  5. 1996 · Treatment · Radiation⚑ needs reviewRTOG 87-04/ECOG: mitomycin added to fluorouracil and radiationA US intergroup trial tested whether adding mitomycin to fluorouracil and radiotherapy helped people with anal canal cancer. At four years fewer people in the mitomycin group had a colostomy (about 9 in 100 versus 22 in 100) and more were free of disease, but severe toxicity was more common.RTOG/ECOG phase III (310 randomised, 291 assessable): radiotherapy 45 to 50.4 Gy with fluorouracil, with or without mitomycin. At 4 years, mitomycin vs fluorouracil-only: disease-free survival 73% vs 51% (P=.0003), colostomy-free survival 71% vs 59% (P=.014), colostomy rate 9% vs 22% (P=.002); grade 4 and 5 toxicity 23% vs 7% (P ≤ .001). No significant overall survival difference at 4 years. Salvage chemoradiation: 12 of 24 assessable disease-free.

Targeted therapy

  1. 1998 · Understanding · UnderstandingAnal HSIL and cancer incidence in people with HIV and MSM cohortsA 1998 San Francisco cohort study found that 49% of HIV-positive and 17% of HIV-negative homosexual and bisexual men (the paper's terms) developed anal precancer (HSIL) within four years. Later North American cohorts reported much higher anal cancer rates with HIV, and a 2024 analysis reported a US decline among people with HIV.Palefsky (AIDS 1998), UCSF cohort of 346 HIV-positive and 262 HIV-negative men: 4-year HSIL incidence 49% (95% CI 41 to 56) vs 17% (12 to 23). Silverberg (CID 2012), 13 North American cohorts: anal cancer per 100,000 person-years 131 in HIV-infected MSM, 46 in other HIV-infected men, 2 in HIV-uninfected men; adjusted RR 80.3 (42.7 to 151.1) for HIV-infected MSM. Deshmukh (JNCI 2024): US incidence among people with HIV fell 2.2% per year.
  2. 2008 · Reversal · RadiationRTOG 98-11: cisplatin-based chemoradiation not superiorA US trial of 682 people compared fluorouracil, mitomycin and radiotherapy with fluorouracil, cisplatin and radiotherapy for anal canal cancer. The first report in 2008 found no significant difference in five-year disease-free or overall survival, and more colostomies with cisplatin. A long-term update in 2012 reported better disease-free and overall survival with mitomycin.RTOG 98-11 (phase 3, N=682; mitomycin-based vs cisplatin-based fluorouracil chemoradiation). 2008 report (median follow-up 2.51 years; 644 assessable): 5-year DFS 60% vs 54% (P=.17), OS 75% vs 70% (P=.10), colostomy 10% vs 19% (P=.02). 2012 long-term update (649 analysable): 5-year DFS 67.8% vs 57.8% (P=.006), OS 78.3% vs 70.7% (P=.026).
  3. 2010 · Detection · Detection & preventionQuadrivalent HPV vaccine: anal cancer and AIN indication (FDA 2010)On 22 December 2010 the US regulator added prevention of anal precancer (AIN) and of anal cancer caused by HPV 16 and 18 to the Gardasil label for ages 9 to 26. The evidence was a randomised trial in 602 young men who have sex with men, which found fewer anal precancers with the vaccine; all cases analysed were precancers.FDA approved a Gardasil supplement on 22 Dec 2010 on the basis of the anal substudy of V501-020 (published in NEJM in 2011): 602 men who have sex with men aged 16 to 26 randomised to quadrivalent vaccine or placebo. Efficacy against HPV 6/11/16/18-related AIN: 50.3% (95% CI 25.7 to 67.2) intention-to-treat, 77.5% (39.6 to 93.3) per-protocol; against grade 2 or 3 AIN: 54.2% (18.0 to 75.3) and 74.9% (8.8 to 95.4).

Immunotherapy

  1. 2012 · Reversal · Radiation⚑ needs reviewACCORD 03: induction chemotherapy and higher boost doseA French trial of 307 people with locally advanced anal canal cancer tested two extra steps: two cycles of chemotherapy before chemoradiation, and a higher radiotherapy boost. Neither showed a clear advantage in being alive without a colostomy at five years.ACCORD 03 (phase 3, 2 × 2 factorial, N=307; tumours 40 mm or more, or under 40 mm with N1-3M0): two cycles of fluorouracil-cisplatin induction or not, and standard (15 Gy) or high-dose (20-25 Gy) boost. Median follow-up 50 months. 5-year colostomy-free survival in arms A to D: 69.6%, 82.4%, 77.1% (reference arm C) and 72.7%. With vs without induction 76.5% vs 75.0% (P=.37); standard vs high-dose boost 73.7% vs 77.8% (P=.067).
  2. 2012 · Treatment · RadiationRTOG 0529: dose-painted IMRT with fluorouracil and mitomycinRTOG 0529 tested dose-painted IMRT, a targeted radiotherapy, with fluorouracil and mitomycin in 63 people with anal canal cancer. It aimed to cut moderate-or-worse bowel and urinary side effects by at least 15% against an earlier trial's conventional arm, and did not meet that goal. Severe skin and bowel effects were less frequent than in that arm, an indirect comparison.RTOG 0529 (phase 2, single-arm; 63 accrued, 52 evaluable; T2-4N0-3M0): dose-painted IMRT with fluorouracil and mitomycin-C. Primary endpoint (at least 15% reduction in acute grade 2+ GI/GU adverse events vs the RTOG 9811 conventional arm) not met: 77% vs 77%. Grade 3+ dermatologic 23% vs 49% (P<.0001); grade 3+ gastrointestinal 21% vs 36% (P=.0082). Median follow-up 7.9 years: 5-year DFS 70%, OS 76%.
  3. 2013 · Reversal · Radiation⚑ needs reviewACT II: cisplatin and maintenance chemotherapy add no benefitACT II, which its authors call the largest anal cancer trial to date, asked two questions in 940 people: does cisplatin work better than mitomycin alongside fluorouracil and radiotherapy, and does further chemotherapy afterwards help? About nine in ten people had a complete response at 26 weeks with either drug, and maintenance did not improve progression-free survival.ACT II (phase 3, open-label, 2 × 2 factorial, N=940): fluorouracil and 50.4 Gy with mitomycin or cisplatin, each with or without two maintenance courses. Complete response at 26 weeks 90.5% vs 89.6% (difference -0.9%, 95% CI -4.9 to 3.1; p=0.64); toxic effects 71% vs 72%. 3-year PFS 74% with vs 73% without maintenance (HR 0.95, 0.75-1.21; p=0.70). Median follow-up 5.1 years.
  4. 2017 · Treatment · Immunotherapy⚑ needs reviewNCI9673: nivolumab for previously treated metastatic anal cancerIn a US phase 2 study of 37 people with treatment-refractory metastatic squamous cell anal cancer, the PD-1 antibody nivolumab shrank tumours in about one in four, including two complete responses. No serious adverse events were reported. The study had no comparison group.Single-arm phase 2 at ten US academic centres: nivolumab 3 mg/kg every 2 weeks in treatment-refractory metastatic SCCA; 39 screened, 37 enrolled and treated. ORR (primary, RECIST 1.1) 24% (95% CI 15-33): 2 complete and 7 partial responses. Grade 3 adverse events: anaemia (n=2), fatigue, rash and hypothyroidism (n=1 each); no serious adverse events reported.
  5. 2018 · Treatment · ChemotherapyEpitopes-HPV02: docetaxel-cisplatin-fluorouracil in advanced diseaseIn a French phase 2 study of 66 treated adults with advanced squamous anal cancer who had not had chemotherapy, a three-drug regimen (docetaxel, cisplatin and fluorouracil) left nearly half alive and without progression at one year. Severe side effects affected seven in ten people and were less frequent with the modified schedule.Single-arm phase 2 at 25 French centres: chemotherapy-naive metastatic or unresectable locally recurrent anal SCC, ECOG 0-1; standard DCF (n=36) or modified DCF (n=30) by clinician recommendation. Primary endpoint met: 31 of 66 (47%) alive and progression-free at 12 months. Grade 3-4 adverse events 70% overall (83% standard, 53% modified); febrile neutropenia in 14% with standard DCF and none with modified DCF.
  6. 2019 · Treatment · SurgerySalvage abdominoperineal resection after chemoradiation: the evidenceWhen anal cancer persists or comes back after chemoradiation, abdominoperineal resection is the usual salvage operation. The evidence is retrospective case series only. A 2019 review of 28 series reported median five-year survival of 45% to 51%, and a 2026 pooled analysis of 18 studies reported five-year survival of 46%, with substantial postoperative morbidity.Ko 2019 systematic review of 28 retrospective case series (9 to 111 patients each): median 5-year OS after salvage APR 45.0% (persistent disease) and 51.0% (recurrent); median 5-year DFS 44.0%; median locoregional recurrence 23.5%. Belfort 2026 meta-analysis of proportions (18 studies, 1,013 patients): pooled 5-year OS 46.43% (95% CI 38.03-55.04); major complications 27.97%; 30-day mortality 1.18%.

Precision & engineered

  1. 2020 · Treatment · ChemotherapyInterAACT: carboplatin-paclitaxel vs cisplatin-fluorouracil, advancedIn 91 adults with advanced anal cancer not yet treated with chemotherapy, carboplatin with paclitaxel and cisplatin with fluorouracil shrank tumours in a similar share, about six in ten. Carboplatin-paclitaxel caused fewer serious side effects, and median survival was longer (about 20 versus 12 months), which the authors called a trend. They suggested it as a new standard of care.Randomised phase 2 (N=91), chemotherapy-naive advanced anal cancer: cisplatin 60 mg/m2 plus fluorouracil (n=46) vs carboplatin AUC 5 plus weekly paclitaxel (n=45). ORR (primary; 35 and 39 response-assessable) 57% vs 59%. Median PFS 5.7 vs 8.1 months; median OS 12.3 vs 20 months (unadjusted HR 2.00 for cisplatin-fluorouracil, 95% CI 1.15-3.47, p=.014). Serious adverse events 62% vs 36% (p=.016).
  2. 2022 · Treatment · Detection & preventionANCHOR: treating anal HSIL in people with HIV vs active monitoringANCHOR randomised people living with HIV, aged 35 or older, who had a biopsy-proven high-grade anal precancer (HSIL), to have it treated or to be monitored without treatment. Anal cancer was diagnosed in 9 people in the treatment group and 21 in the monitoring group. It tested treating a known precancer, not screening itself.ANCHOR (NEJM 2022): phase 3, 25 US sites; people with HIV aged 35 or older and biopsy-proven anal HSIL randomised 1:1 to HSIL treatment or active monitoring; 4446 of 4459 analysed, median follow-up 25.8 months. Progression to anal cancer: 9 cases (173 per 100,000 person-years, 95% CI 90 to 332) with treatment vs 21 (402, 262 to 616) with monitoring; rate 57% lower (95% CI 6 to 80; P=0.03, log-rank).
  3. 2022 · Treatment · ImmunotherapyKEYNOTE-158: pembrolizumab in previously treated anal carcinomaIn the anal cancer cohort of the phase 2 KEYNOTE-158 study, 112 people with previously treated advanced squamous cell cancer received the PD-1 antibody pembrolizumab. About one in nine had a tumour response, mostly in people whose tumours were PD-L1-positive. The study had no comparison group.Non-randomised multicohort phase 2, anal SCC cohort A (38 centres across all cohorts): pembrolizumab 200 mg every 3 weeks for up to 2 years in 112 patients enrolled and treated after failure of or intolerance to standard therapy, or with none available. ORR (primary, RECIST 1.1) 11% (95% CI 6-18); 15% (8-25) in 75 with PD-L1-positive tumours; 3% (0-17) in 30 with PD-L1-negative tumours. Grade 3-4 adverse events 18%; data cutoff 27 June 2019.
  4. 2022 · Treatment · ImmunotherapyPOD1UM-202: retifanlimab after platinum chemotherapyIn a phase 2 study of 94 people with squamous anal cancer that had progressed after platinum chemotherapy, the PD-1 antibody retifanlimab shrank tumours in about one in seven. The FDA approved single-agent use in May 2025; the EU product information lists only the first-line combination.Single-arm phase 2 (N=94), SCAC progressed after or ineligible for platinum chemotherapy: retifanlimab 500 mg every 4 weeks. ORR (primary, independent review) 13.8% (95% CI 7.6-22.5): 1 complete and 12 partial responses; median DOR 9.5 months; median PFS 2.3 months and OS 10.1 months at median follow-up 7.1 months. FDA label ORR 14% (95% CI 8-23). Single-agent indication approved 15 May 2025.
  5. 2024 · Detection · Detection & preventionIANS consensus guidelines: risk-based anal cancer screeningIn 2024 the International Anal Neoplasia Society published consensus guidelines on who should be screened for anal cancer. They set starting ages by risk group, such as 35 for men who have sex with men and transgender women with HIV and 45 for other people with HIV, and describe the tests and when to refer for anoscopy.IANS consensus guideline (Int J Cancer 2024) with risk thresholds drawn from age-specific anal cancer incidence estimates by group. Screening from age 35: MSM and transgender women with HIV; from 45: other people with HIV, and MSM and transgender women without HIV; from 10 years after solid organ transplant; within 1 year of vulvar precancer or cancer. Cytology, hrHPV testing or co-testing; referral thresholds for high-resolution anoscopy are delineated.
  6. 2025 · Treatment · RadiationPLATO-ACT4: reduced-dose chemoradiotherapy, 6-month resultsPLATO-ACT4 is testing whether a lower radiotherapy dose is enough for small anal cancers without lymph node spread. The first report covers six months: about nine in ten people had a complete clinical response with either dose. Whether the cancer stays away with the lower dose is the main question, and those three-year results are still awaited.PLATO-ACT4 (phase 2, two-arm non-comparative randomised 1:2; T1-2 up to 4 cm, N0-Nx, M0; 160 in the primary analysis): standard-dose IMRT 50.4 Gy in 28 fractions vs reduced-dose 41.4 Gy in 23 fractions, with mitomycin and capecitabine. Six-month complete clinical response 87% (46 of 53) vs 92% (89 of 97); grade 3 or worse acute toxicity 46% vs 35%. The primary outcome, 3-year locoregional failure, is awaited.
  7. 2025 · Treatment · ImmunotherapyRetifanlimab plus carboplatin-paclitaxel, first line (POD1UM-303)In 308 adults with squamous anal cancer that had come back or spread and had not yet been treated with chemotherapy, adding the immune therapy retifanlimab to carboplatin and paclitaxel delayed progression, from about seven months to about nine. The final survival comparison favoured retifanlimab (about 33 versus 22 months) but did not reach statistical significance.Phase 3, double-blind, N=308, chemotherapy-naive inoperable locally recurrent or metastatic SCAC: carboplatin-paclitaxel plus retifanlimab 500 mg or placebo every 4 weeks. Primary PFS (independent review): median 9.3 vs 7.4 months, HR 0.63 (95% CI 0.47-0.84), one-sided p=0.0006. Interim OS HR 0.70 (0.49-1.01); final OS median 32.8 vs 22.2 months, HR 0.75 (0.55-1.01), not significant; 77 placebo patients crossed over. Grade 3 or worse adverse events 83.1% vs 75.0%.
  8. 2026 · Reversal · ImmunotherapyNCI9673 Part B: ipilimumab added to nivolumab, no gain shownIn a randomised phase 2 study of 100 people with refractory, incurable anal cancer, adding ipilimumab to nivolumab did not significantly improve response, progression-free survival or overall survival. Severe (grade 3 or worse) treatment-related side effects were about twice as frequent with the combination: about one in four people versus one in eight.Randomised phase 2 (N=100; 52 vs 48), refractory incurable anal cancer: nivolumab 480 mg every 4 weeks alone or with ipilimumab 1 mg/kg every 8 weeks. Primary PFS (one-sided alpha 0.1): median 2.9 vs 3.7 months, HR 0.86 (interval 0.60-1.23), P=.25. Response rate 17.4% vs 21.5% (P=.89). Median OS 15.9 vs 20.0 months, HR 0.98 (90% CI 0.63-1.51). Grade 3 or worse treatment-related adverse events 12% vs 25%.

Then and now

  • 5-year relative survival · United States, SEER 8 registries

    • 63.28%

      1975 (observed value)

    • 71.27%

      2018 (observed value; last observed year in the table)

    Anal cancer, all races, both sexes; the SEER 8 five-year relative survival series (1975-2018) on the SEER Cancer Stat Facts anal cancer page. The page states no age range or stage mix for this series.

    Relative survival excludes deaths from other causes. 'Observed' is the table's label for the yearly value, as opposed to the Joinpoint modelled-trend value in the adjacent column. The column is headed 'Year' and the chart note says only '1975-2018'; the page does not say the year is the year of diagnosis. The page gives no case counts or confidence intervals for the yearly values, and the observed values swing widely from year to year (from 48.64% in 1981 to 75.96% in 2016): a single year is a noisy starting or end point, and the modelled-trend values for the same two years (56.87% in 1975, 73.11% in 2018) are shown separately. Survival measured from diagnosis can change with earlier detection and case mix as well as with treatment, and the page does not say how much of the change in this series is due to treatment, stage at diagnosis or other factors, so it is not a measure of treatment effect; read it beside the mortality values. Observed values are used because the 2019-2023 entries in the table are modelled-trend values only. Compare only with other values from this same SEER 8 series.

    Source

  • 5-year relative survival · United States, SEER 8 registries

    • 56.87%

      1975 (modelled-trend value)

    • 73.11%

      2018 (modelled-trend value)

    Joinpoint modelled-trend values for the same SEER 8 anal cancer series (all races, both sexes).

    These are fitted values: the page's chart note says the trend lines were calculated from the underlying rates with Joinpoint Survival Model software, so they are model output, not observations, and they smooth the year-to-year variation in the observed values (shown separately). The table also prints modelled values for 2019-2023 (73.42% to 74.64%) for years with no observed value. The same limits apply as for the observed values: the page does not say the year is the year of diagnosis and does not attribute the rise to any cause. Compare only with other values from this same SEER 8 series.

    Source

  • 5-year relative survival · United States, SEER 21 (excluding IL)

    • 70.9%

      2016-2022, all stages

    • 85%

      2016-2022, localized stage

    • 70.1%

      2016-2022, regional stage

    • 36.5%

      2016-2022, distant stage

    • 65.1%

      2016-2022, unstaged

    Anal cancer, all races, both sexes; SEER 21 (excluding IL), 2016-2022; stage-specific values use SEER Combined Summary Stage. Stage mix in the page's stage table: localized 39%, regional 38%, distant 14%, unstaged 8% (the page text gives 39.5% localized).

    Relative survival excludes deaths from other causes. This is a different registry set and period from the SEER 8 series above: do not splice the two or subtract one from the other. The page's 'At a Glance' figure (70.9%) and its survival-by-stage table use this series. The page says stage at diagnosis has a strong influence on the length of survival; stage-specific values describe the extent of disease at diagnosis and are not a measure of treatment effect.

    Source

  • Age-standardised mortality · United States

    • 0.04per 100,000

      1975 (observed value)

    • 0.37per 100,000

      2024 (observed value; latest year in the table)

    Anal cancer, all races, both sexes; age-adjusted death rate from US mortality data (the 'Death Rate - U.S.' column of the page's table), not SEER registry data.

    Death rates describe the whole US population and are not measured from the date of diagnosis, so they are not affected by lead time the way survival from diagnosis is; the page attributes the change to no cause (incidence, detection, treatment and coding all act on this rate). The 1975 rate is very low, so percentage changes from that year are not meaningful. The modelled-trend values are 0.03 (1975) and 0.40 (2024); the highest observed value is 0.40 (2021), followed by 0.38 (2022) and 0.37 in both 2023 and 2024. The page text says age-adjusted death rates have been rising on average 3.9% each year over 2015-2024 and gives 0.4 per 100,000 for 2020-2024 deaths. Survival (above) and mortality measure different things and are shown together, not combined.

    Source

Survival figures are affected by earlier detection (lead time) and overdiagnosis, and by changes in who is diagnosed. For screened cancers, read them alongside mortality.

Evidence chains

A lane follows one defined population and setting, where each new trial tests against what was then standard. Compare only within a lane, and read every comparison as illustrative.

Anal cancer: radiotherapy alone versus chemoradiation

Adults with epidermoid (squamous) anal cancer treated with radiotherapy alone or with radiotherapy plus fluorouracil and mitomycin. Entry rules differ: ACT I included anal canal and anal margin cancers, with T1 tumours; EORTC 22861 enrolled T3-4 N0-3 or T1-2 N1-3 disease. · Localised · endpoint: Locoregional failure

Results are not comparable across trials.

Lower is better. Only ACT I is drawn: the value is its 5-year locoregional relapse rate from the 13-year follow-up report, radiotherapy alone versus radiotherapy with fluorouracil and mitomycin. The 'local failure' measure in ACT I's original 1996 report is defined differently and is not mixed with it. EORTC 22861 is listed but not drawn: its abstract gives complete response of the primary tumour, a different endpoint, and no arm-level locoregional values. Nigro's 1974 report is a single-arm series with no comparison group, so it has no entry. The two randomised trials differ in eligibility and radiotherapy schedule: EORTC 22861 gave 45 Gy, a 6-week rest, then a boost, while ACT I gave 45 Gy with a boost for good responders and salvage surgery for poor responders. Compare only each trial's own two arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

020406080100Locoregional failure at 60 months (%)1996ACT I
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
Locoregional failure at 60 months, rate, across 1 trial in this lane. ACT I (1996): experimental 32.3 % vs control 57.1 %.
Data table
TrialYearEndpointControl (%)Experimental (%)
ACT I1996Locoregional failure57.1 %32.3 %

Anal canal cancer, definitive chemoradiation: mitomycin, cisplatin and treatment intensity

Adults with carcinoma of the anal canal treated with definitive chemoradiation. Entry rules differ: epidermoid carcinoma (RTOG/ECOG), anal canal carcinoma stratified by sex, node status and tumour diameter (RTOG 98-11), squamous cell carcinoma of the anus from 59 UK centres (ACT II), T2-4 N0-3 M0 disease (RTOG 0529) and locally advanced disease (ACCORD 03). · Locally advanced · endpoint: DFS

Results are not comparable across trials.

Higher is better for disease-free survival. The entries ask different questions and have different controls. The RTOG/ECOG trial tested adding mitomycin to fluorouracil and radiotherapy (control: fluorouracil chemoradiation); RTOG 98-11 and ACT II tested cisplatin in place of mitomycin (control: mitomycin chemoradiation). Endpoints and time points also differ: RTOG/ECOG is 4-year disease-free survival; RTOG 98-11 is 5-year disease-free survival from its 2008 primary report (its 2012 long-term update is a separate result that reached a different conclusion on disease-free and overall survival and is not drawn); ACT II is complete response at 26 weeks, a response rate, pooled across its maintenance groups and drawn with a distinct marker. Cisplatin was given as induction plus concurrent treatment in RTOG 98-11 but concurrently only in ACT II, which was also a 2 x 2 factorial with a maintenance factor (not drawn). Only entries at the same landmark share the axis; the others are listed. RTOG 0529 is a single-arm phase 2 trial compared with the mitomycin arm of RTOG 98-11 in a cross-trial comparison, and ACCORD 03 (induction chemotherapy and boost dose, colostomy-free survival) has no disease-free survival result; both are listed without entries. ACCORD 03 stays marked for review: an erratum to its report has not been read, so its patient count is unconfirmed. Eras, eligibility and radiotherapy technique differ; compare only each trial's own arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

020406080100DFS at 48 months (%)1996RTOG 87-04/ECOG
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
DFS at 48 months, rate, across 1 trial in this lane. RTOG 87-04/ECOG (1996): experimental 73 % vs control 51 %.
Data table
TrialYearEndpointControl (%)Experimental (%)
RTOG 87-04/ECOG1996DFS51 %73 %
RTOG 98-112008DFS (not plotted: different measure or time point)60 %54 %
ACT II2013Complete response of the primary tumour (differs from lane) (not plotted: different measure or time point)90.5 %89.6 %

Advanced anal squamous cell carcinoma, first-line systemic therapy

Adults with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal who had not received systemic therapy for advanced disease (InterAACT; POD1UM-303, which allowed HIV if well controlled). · Metastatic · endpoint: PFS

Results are not comparable across trials.

Eras, designs, control arms and review methods differ and medians must not be chained across trials. InterAACT (2013 to 2017) was a randomised phase 2 trial whose primary endpoint was response rate; progression-free survival was a secondary endpoint in a hierarchical model, and its difference was not statistically significant (unadjusted hazard ratio 1.27, 95% CI 0.75-2.14; the paper does not name the reference arm). The paper names no control arm, so the control and experimental roles shown are a display convention. Its response rate was analysed in a modified intention-to-treat population (35 and 39 patients), and its overall survival hazard ratio (2.00 unadjusted; 1.78 adjusted for stratification factors, with an interval that includes 1) was a secondary, exploratory result with few events. POD1UM-303 was a double-blind phase 3 trial of retifanlimab or placebo added to carboplatin-paclitaxel, with independently assessed progression-free survival as the primary endpoint and well-controlled HIV allowed; the plotted values are its primary analysis. The two trials differ in era, eligibility and endpoint, so only each trial's own arms are comparable. Epitopes-HPV02 is a single-arm phase 2 study of docetaxel, cisplatin and fluorouracil and is listed without an entry.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

02468101214PFS, median (months)20202025InterAACTPOD1UM-303
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
PFS, median, across 2 trials in this lane. InterAACT (2020): experimental 8.1 months vs control 5.7 months; POD1UM-303 (2025): experimental 9.3 months vs control 7.4 months.
Data table
TrialYearEndpointControl (months)Experimental (months)
InterAACT2020PFS5.7 months8.1 months
POD1UM-3032025PFS7.4 months9.3 months

Advanced anal squamous cell carcinoma after prior systemic therapy

Adults with refractory, incurable anal cancer who had received at least one previous systemic therapy (NCI9673 Part B also required no previous immunotherapy). The single-arm studies listed here enrolled people who had progressed after, or could not receive, standard therapy. · Relapsed / refractory · endpoint: PFS

Results are not comparable across trials.

NCI9673 Part B is the only randomised comparison in this setting and the only entry: nivolumab with ipilimumab versus nivolumab alone, with progression-free survival as the primary endpoint. Its published confidence intervals for the medians are 90% intervals, and its control is an anti-PD-1 antibody, not placebo or chemotherapy. This lane is kept apart from first-line therapy because the populations differ. NCI9673 Part A, POD1UM-202 and the KEYNOTE-158 anal cancer cohort are single-arm studies that report response rates without a comparison group; they are listed without entries and should not be compared with each other or with Part B, since prior-therapy rules, response criteria and follow-up differ. The NCI9673 Part A milestone stays marked for review because its published 95% confidence interval for the response rate does not match the stated method. Compare only each trial's own arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

012345PFS, median (months)2026NCI9673 Part B
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
PFS, median, across 1 trial in this lane. NCI9673 Part B (2026): experimental 3.7 months vs control 2.9 months.
Data table
TrialYearEndpointControl (months)Experimental (months)
NCI9673 Part B2026PFS2.9 months3.7 months

Anal HSIL in people with HIV: treatment versus active monitoring

People living with HIV aged 35 or older with biopsy-proven anal high-grade squamous intraepithelial lesions (HSIL), enrolled at 25 US sites (ANCHOR). · Prevention · endpoint: Progression to anal cancer

Results are not comparable across trials.

Lower is better. ANCHOR compares treating biopsy-proven HSIL with active monitoring in people living with HIV aged 35 or older; it is not a test of screening itself. It is the only randomised trial in this lane, so there is no comparison across trials. The plotted values are the 48-month cumulative incidence of anal cancer in the two arms, shown without confidence intervals. The result applies to the trial population and should not be read for other groups.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

020406080100Progression to anal cancer at 48 months (%)2022ANCHOR
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
Progression to anal cancer at 48 months, rate, across 1 trial in this lane. ANCHOR (2022): experimental 0.9 % vs control 1.8 %.
Data table
TrialYearEndpointControl (%)Experimental (%)
ANCHOR2022Progression to anal cancer1.8 %0.9 %

Standard of care, then and now

How the usual sequence of treatment changed for one setting. Choose a point in time; each step links to the milestone behind it.

Anal canal cancer: definitive treatment

Adults with squamous cell carcinoma of the anal canal considered for definitive treatment; entry criteria differ by trial · Localised

  1. Radiation1Chemoradiation rather than RT aloneACT I and EORTC 22861: radiotherapy alone vs chemoradiation (1996)
  2. Chemotherapy2Mitomycin added to fluorouracilRTOG 87-04/ECOG: mitomycin added to fluorouracil and radiation (1996)
  3. Radiation3Dose-painted IMRT (single-arm trial)RTOG 0529: dose-painted IMRT with fluorouracil and mitomycin (2012)
Today. Based only on the trials cited in each step. PLATO-ACT4 reported 6-month results of reduced-dose radiotherapy for early-stage disease in 2025; its 3-year locoregional failure result is awaited, so no step is added.
Text version
  • 1941: Radium needling or rectal excision
  • 1974: Radium needling or rectal excision → Chemotherapy with radiation (preliminary)
  • 1996: Chemoradiation rather than RT alone → Mitomycin added to fluorouracil
  • 2013: Chemoradiation rather than RT alone → Mitomycin added to fluorouracil → Dose-painted IMRT (single-arm trial)
  • Today: Chemoradiation rather than RT alone → Mitomycin added to fluorouracil → Dose-painted IMRT (single-arm trial)

Advanced anal cancer: systemic therapy

Adults with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal; entry criteria differ by trial · Metastatic

  1. Chemotherapy1Cisplatin with fluorouracil (small series)Platinum-fluoropyrimidine chemotherapy in metastatic anal cancer (1989)
  2. Chemotherapy2DCF chemotherapy (single-arm phase 2)Epitopes-HPV02: docetaxel-cisplatin-fluorouracil in advanced disease (2018)
  3. Chemotherapy3Carboplatin plus paclitaxelInterAACT: carboplatin-paclitaxel vs cisplatin-fluorouracil, advanced (2020)
  4. Immunotherapy4Retifanlimab plus carboplatin-paclitaxelRetifanlimab plus carboplatin-paclitaxel, first line (POD1UM-303) (2025)
  5. Immunotherapy5Nivolumab in refractory disease (single-arm)NCI9673: nivolumab for previously treated metastatic anal cancer (2017)
  6. Immunotherapy6Pembrolizumab after prior therapy (cohort)KEYNOTE-158: pembrolizumab in previously treated anal carcinoma (2022)
Today. Based only on the trials cited in each step. The FDA approved retifanlimab with carboplatin-paclitaxel in May 2025 and the EU followed in March 2026; pembrolizumab was studied after progression in a single-arm cohort.
Text version
  • 1999: Cisplatin with fluorouracil (small series)
  • 2020: Cisplatin with fluorouracil (small series) → DCF chemotherapy (single-arm phase 2) → Carboplatin plus paclitaxel → Nivolumab in refractory disease (single-arm)
  • Today: Cisplatin with fluorouracil (small series) → DCF chemotherapy (single-arm phase 2) → Carboplatin plus paclitaxel → Retifanlimab plus carboplatin-paclitaxel → Nivolumab in refractory disease (single-arm) → Pembrolizumab after prior therapy (cohort)

Reversals and dead ends

Approaches that were abandoned or withdrawn, and trials whose results were later questioned, are part of the story.

  • 2008

    RTOG 98-11: cisplatin-based chemoradiation not superior

    A US trial of 682 people compared fluorouracil, mitomycin and radiotherapy with fluorouracil, cisplatin and radiotherapy for anal canal cancer. The first report in 2008 found no significant difference in five-year disease-free or overall survival, and more colostomies with cisplatin. A long-term update in 2012 reported better disease-free and overall survival with mitomycin.

    RTOG 98-11 (phase 3, N=682; mitomycin-based vs cisplatin-based fluorouracil chemoradiation). 2008 report (median follow-up 2.51 years; 644 assessable): 5-year DFS 60% vs 54% (P=.17), OS 75% vs 70% (P=.10), colostomy 10% vs 19% (P=.02). 2012 long-term update (649 analysable): 5-year DFS 67.8% vs 57.8% (P=.006), OS 78.3% vs 70.7% (P=.026).

  • 2012

    ACCORD 03: induction chemotherapy and higher boost dose

    A French trial of 307 people with locally advanced anal canal cancer tested two extra steps: two cycles of chemotherapy before chemoradiation, and a higher radiotherapy boost. Neither showed a clear advantage in being alive without a colostomy at five years.

    ACCORD 03 (phase 3, 2 × 2 factorial, N=307; tumours 40 mm or more, or under 40 mm with N1-3M0): two cycles of fluorouracil-cisplatin induction or not, and standard (15 Gy) or high-dose (20-25 Gy) boost. Median follow-up 50 months. 5-year colostomy-free survival in arms A to D: 69.6%, 82.4%, 77.1% (reference arm C) and 72.7%. With vs without induction 76.5% vs 75.0% (P=.37); standard vs high-dose boost 73.7% vs 77.8% (P=.067).

  • 2013

    ACT II: cisplatin and maintenance chemotherapy add no benefit

    ACT II, which its authors call the largest anal cancer trial to date, asked two questions in 940 people: does cisplatin work better than mitomycin alongside fluorouracil and radiotherapy, and does further chemotherapy afterwards help? About nine in ten people had a complete response at 26 weeks with either drug, and maintenance did not improve progression-free survival.

    ACT II (phase 3, open-label, 2 × 2 factorial, N=940): fluorouracil and 50.4 Gy with mitomycin or cisplatin, each with or without two maintenance courses. Complete response at 26 weeks 90.5% vs 89.6% (difference -0.9%, 95% CI -4.9 to 3.1; p=0.64); toxic effects 71% vs 72%. 3-year PFS 74% with vs 73% without maintenance (HR 0.95, 0.75-1.21; p=0.70). Median follow-up 5.1 years.

  • 2026

    NCI9673 Part B: ipilimumab added to nivolumab, no gain shown

    In a randomised phase 2 study of 100 people with refractory, incurable anal cancer, adding ipilimumab to nivolumab did not significantly improve response, progression-free survival or overall survival. Severe (grade 3 or worse) treatment-related side effects were about twice as frequent with the combination: about one in four people versus one in eight.

    Randomised phase 2 (N=100; 52 vs 48), refractory incurable anal cancer: nivolumab 480 mg every 4 weeks alone or with ipilimumab 1 mg/kg every 8 weeks. Primary PFS (one-sided alpha 0.1): median 2.9 vs 3.7 months, HR 0.86 (interval 0.60-1.23), P=.25. Response rate 17.4% vs 21.5% (P=.89). Median OS 15.9 vs 20.0 months, HR 0.98 (90% CI 0.63-1.51). Grade 3 or worse treatment-related adverse events 12% vs 25%.

Today and tomorrow

Standard of care today

Prevention
HPV vaccination. The FDA approved a Gardasil supplement on 22 December 2010 (letter BL 125126/1895) to add prevention of anal intraepithelial neoplasia (AIN) grades 1 to 3 caused by the vaccine's HPV types, and of anal cancer caused by HPV types 16 and 18, in males and females 9 through 26 years of age. The current Gardasil 9 label (DailyMed version 31, effective 13 July 2026; label text revised 03/2025) lists, for girls and women and for boys and men 9 through 45 years of age, prevention of anal cancers caused by HPV types 16, 18, 31, 33, 45, 52 and 58 and of AIN grades 1 to 3; its accelerated-approval wording applies to the oropharyngeal and other head and neck cancer indication, not to the anal indications. The label also states that vaccination does not remove the need for screening. The efficacy evidence behind the 2010 anal indication was a randomised trial in men who have sex with men with AIN as the endpoint (V501-020 anal substudy); an FDA review reports that no anal cancer occurred among the cases in its primary analysis.
U 2010National Library of Medicine, DailyMed 2026Palefsky JM, Giuliano AR, Goldstone S, Moreira ED Jr, Aranda C, Jessen H, et al 2011U 2010
Screening
Risk-targeted screening is addressed by the International Anal Neoplasia Society (IANS) consensus guideline (Stier et al, Int J Cancer 2024); only its abstract was read. The abstract recommends starting screening at age 35 for men who have sex with men and transgender women with HIV; at 45 for other people with HIV and for men who have sex with men and transgender women without HIV; from 10 years after solid organ transplant; and within 1 year of a diagnosis of vulvar precancer or cancer. It says people aged 45 or older with a history of cervical or vaginal HSIL or cancer, perianal warts, persistent cervical HPV16 or autoimmune conditions could be considered for screening with shared decision-making, provided there is capacity for high-resolution anoscopy. It describes anal cytology, high-risk HPV testing (including HPV16 genotyping) and co-testing as strategies with acceptable performance. The randomised evidence concerns treatment of a precancer already found: in ANCHOR (people living with HIV aged 35 or older with biopsy-proven HSIL) anal cancer was diagnosed in 9 people given treatment and 21 monitored without treatment; screening itself was not randomised. Other societies' screening positions (for example NCCN or HIV guidelines) are not summarised here.
Stier EA, Clarke MA, Deshmukh AA, Wentzensen N, Liu Y, Poynten IM, et al 2024Palefsky JM, Lee JY, Jay N, Goldstone SE, Darragh TM, Dunlevy HA, et al 2022
Localised

Chemoradiation is the primary treatment for squamous cell carcinoma of the anal canal, as the sources below describe it. The ASTRO guideline (Feng et al, Pract Radiat Oncol 2025; only its abstract was read) recommends definitive combined modality therapy for most patients, using concurrent fluorouracil or capecitabine plus mitomycin, with cisplatin as a conditional alternative to mitomycin; says select early-stage disease may be considered for local excision alone; and recommends intensity-modulated radiotherapy-based approaches. The NCI PDQ summary (updated 12 February 2025; it states it is not a guideline) names wide local excision for small tumours of the perianal skin or anal margin and chemoradiation (fluorouracil and mitomycin, capecitabine and mitomycin, or fluorouracil and cisplatin, each with radiation) as the standard for other stage I to III cancers. In randomised trials cisplatin in place of mitomycin did not improve outcomes:

  • in RTOG 98-11 the original report found no gain in disease-free survival and a worse colostomy rate, and the long-term update reported better disease-free and overall survival with mitomycin
  • in ACT II complete response at 26 weeks was 90.5% with mitomycin and 89.6% with cisplatin. A 2026 ASCO Educational Book review abstract states that alternative chemotherapy, induction therapy or radiation dose escalation did not improve outcomes. Radiation dose reduction is under study: in the non-comparative randomised phase 2 PLATO ACT4, 6-month complete clinical response was 92% (89 of 97) with 41.4 Gy and 87% (46 of 53) with 50.4 Gy in early-stage disease, and the primary outcome, 3-year locoregional failure, is awaited. For persistent or recurrent disease, salvage abdominoperineal resection rests on observational series (a 2026 meta-analysis of 18 observational studies pooled 5-year overall survival at 46.43%, 95% CI 38.03 to 55.04). The ESMO Clinical Practice Guideline (Rao et al, Ann Oncol 2021) is cited by identifier only
  • its text was not read
Feng M, Hallemeier CL, Almada C, Aranha O, Dorth J, Felder S, et al 2025National Cancer Institute 2025Ajani JA, Winter KA, Gunderson LL, Pedersen J, Benson AB 3rd, Thomas CR Jr, et al 2008Gunderson LL, Winter KA, Ajani JA, Pedersen JE, Moughan J, Benson AB 3rd, et al 2012James RD, Glynne-Jones R, Meadows HM, Cunningham D, Myint AS, Saunders MP, et al 2013Fernando S, Morris V, Yu J, Eng C, Lessans S, Rao S 2026Gilbert A, Adams R, Webster J, Gilbert DC, Abbott NL, Berkman L, et al 2025Belfort GR, Pompeu BF, Velucci MP, Baptista CH, Delgado LM, Marques FILCB, et al 2026Rao S, Guren MG, Khan K, Brown G, Renehan AG, Steigen SE, et al 2021
Metastatic

First-line treatment of inoperable locally recurrent or metastatic disease. FDA:

  • on 15 May 2025 (BLA 761334/S-004) retifanlimab-dlwr (Zynyz) was approved in combination with carboplatin and paclitaxel for first-line treatment of adults with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal. The letter says only that the supplement is approved and has no accelerated-approval section, and the accelerated-approval statement in the 05/2025 label concerns Merkel cell carcinoma only, so treating the approval as regular is an inference from the absence of that wording. Supplement S-008 (30 March 2026) added a 375 mg every 3 weeks regimen, and S-009 (18 May 2026) updated the label with the final POD1UM-303 report and recorded the postmarketing commitment as fulfilled
  • the 05/2026 label states overall survival results were not statistically significant. EU: the European Commission decision of 5 March 2026 (CHMP opinion 29 January 2026) extended the Zynyz indication to this first-line combination with carboplatin and paclitaxel. Carboplatin with paclitaxel was compared with cisplatin with fluorouracil in the randomised phase 2 InterAACT trial (91 randomised). A 2026 ASCO Educational Book review abstract describes carboplatin-paclitaxel as the established first-line chemotherapy backbone and retifanlimab with chemotherapy as a preferred first-line approach. The NCI PDQ summary (updated 12 February 2025, before the retifanlimab approval) lists carboplatin with paclitaxel, cisplatin with fluorouracil, and docetaxel with cisplatin and fluorouracil among stage IV options. The ESMO guideline (Rao et al, Ann Oncol 2021) is cited by identifier only
  • its text was not read
U 2025U 2025U 2026U 2026U 2026EMA 2026European Medicines Agency, CHMP 2026European Medicines Agency 2026Rao S, Sclafani F, Eng C, Adams RA, Guren MG, Sebag-Montefiore D, et al 2020Fernando S, Morris V, Yu J, Eng C, Lessans S, Rao S 2026National Cancer Institute 2025Rao S, Guren MG, Khan K, Brown G, Renehan AG, Steigen SE, et al 2021
Relapsed / refractory

After platinum-based chemotherapy. FDA:

  • the same 15 May 2025 letter approved retifanlimab-dlwr as a single agent for adults with locally recurrent or metastatic squamous cell carcinoma of the anal canal with disease progression on or intolerance to platinum-based chemotherapy
  • the evidence was the single-arm POD1UM-202 study, and neither the letter nor the label carries accelerated-approval wording for this indication (recorded as regular, an inference). EU: the Zynyz summary of product characteristics (section 4.1) lists the anal canal indication only in combination with carboplatin and paclitaxel for first-line treatment, with no single-agent anal cancer indication. Nivolumab and pembrolizumab have phase 2 data in this disease (NCI9673 Part A
  • the KEYNOTE-158 anal cohort), but the Indications and Usage sections of their current FDA labels (openFDA records effective 12 August 2026 and 10 July 2026) do not name anal cancer (the pembrolizumab label also lists site-agnostic indications for MSI-H or dMMR and for TMB-H solid tumours). The NCI PDQ summary (updated 12 February 2025) lists nivolumab and pembrolizumab among stage IV options. A 2026 ASCO Educational Book review abstract states that anti-PD-1 monotherapy gives modest response rates in the treatment-refractory setting and remains a standard option for people not previously given immunotherapy
U 2025U 2025European Medicines Agency 2026Morris VK, Salem ME, Nimeiri H, Iqbal S, Singh P, Ciombor K, et al 2017Marabelle A, Cassier PA, Fakih M, Kao S, Nielsen D, Italiano A, et al 2022U 2026U 2026National Cancer Institute 2025Fernando S, Morris V, Yu J, Eng C, Lessans S, Rao S 2026

Trials to watch

  • EA2176 NCT04444921

    In untreated metastatic anal cancer (the registry's official title says 'Treatment-Naive Metastatic Anal Cancer Patients'; eligibility also admits inoperable or recurrent anal squamous cell carcinoma not amenable to curative therapy), does adding nivolumab to carboplatin and paclitaxel improve progression-free survival (the registry's primary outcome) compared with carboplatin and paclitaxel alone? Registry record: randomised open-label phase 3, 205 estimated, sponsor National Cancer Institute (ECOG-ACRIN identifier EA2176). Registry status: active, not recruiting; primary completion estimated March 2027; no results posted.

  • EA2165 NCT03233711

    In high-risk anal squamous cell carcinoma after combined modality therapy (registry eligibility: AJCC 8th edition stage IIB to IIIC), does nivolumab improve disease-free survival (the registry's primary outcome) compared with clinical observation? Registry record: randomised open-label phase 3, 344 estimated, sponsor National Cancer Institute (ECOG-ACRIN identifier EA2165). Registry status: active, not recruiting; primary completion estimated December 2027; no results posted.

  • KANALRAD (PRODIGE 85) NCT06207981

    In locally advanced anal squamous cell carcinoma (T3-4 or node-positive, no metastases), does induction chemotherapy with modified DCF (docetaxel, cisplatin and fluorouracil; 4 cycles) before chemoradiotherapy improve disease-related event-free survival at 2 years (the registry's primary outcome) compared with standard chemoradiotherapy? Registry record: randomised open-label phase 3, 310 estimated, sponsor Federation Francophone de Cancerologie Digestive. Registry status: recruiting (status last verified February 2025); primary completion estimated February 2029; no results posted.

  • Sintilimab-based chemoradiation (NCC6140) NCT07692152

    In limited-stage anal squamous cell carcinoma, how does sintilimab with capecitabine and intensity-modulated radiotherapy, used in place of mitomycin, compare with mitomycin, capecitabine and intensity-modulated radiotherapy for clinical complete response rate 6 months after radiotherapy and for grade 3 or worse acute adverse events (the registry's two primary outcomes)? Registry record: randomised open-label phase 3, 350 estimated, sponsor Cancer Institute and Hospital, Chinese Academy of Medical Sciences; eligibility also admits a subset of rectal squamous cell carcinomas. Registry status: recruiting (started March 2026); primary completion estimated March 2029; no results posted.

References

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Every figure was checked against its primary source to the extent possible. Items that could not be fully confirmed are marked “needs review”. Educational history, not medical advice.

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Links open the primary source. A flag marked ⚑ needs review means a value or claim has not yet been independently confirmed.

1987UnderstandingUnderstanding

majorAny settingNeeds review

HPV 16 DNA in anal squamous cell carcinoma, 1987 to 1989

A 1987 Lancet letter titled 'Human papillomavirus type 16 DNA in anal squamous cell carcinoma' has no abstract. A 1989 series found HPV 16 DNA in 23 of 41 such cancers and in no non-malignant anal tissue; another 1989 study described anal precancer (AIN) as a possible parallel to cervical precancer.

Palmer (Lancet 1987 letter): HPV 16 DNA in anal squamous cell carcinoma (title only; no abstract). Palmer (Dis Colon Rectum 1989): 45 primary anal malignancies tested by Southern and dot blot; HPV 16 DNA in 23 of 41 squamous cell carcinomas (56%), HPV 18 in 2 of 41 (5%), HPV 6 or 11 in none. Scholefield (Lancet 1989): AIN in 23 of 82 patients with anal HPV infection; 17 of 28 homosexual vs 1 of 26 heterosexual men.

Why it mattered

Anal squamous carcinomas were found to carry HPV types associated with cervical and other genital cancers, and an anal counterpart of cervical precancer was described; later entries on anal precancer and screening take up both points.

Caveats

  • The 1987 Lancet letter has no abstract in PubMed and is cited by its title only, so its method, number of tumours and findings are not described here. The detection method (Southern and dot blot) and the counts are from the 1989 abstract.
  • No source read states that this was the first report of HPV in anal cancer, so no priority is claimed.
  • Detecting viral DNA in tumour tissue shows the virus is present; it does not by itself show cause. The 1989 authors wrote that their results lend support to a role for HPV 16 and 18 in anal and genital squamous cell carcinoma.
  • The Scholefield study examined patients by endoscopy and biopsy, found anal intraepithelial neoplasia in patients with anal HPV infection and none in the 20 control patients with fissure or fistula, and called for further studies of natural history; its title poses the cervical comparison as a 'possible parallel'.
  • The earlier cervical findings for HPV 16 and 18 are in the Foundations timeline.